Cancer patients undergoing treatment with cytotoxic chemotherapeutic agents often experience a constellation of symptoms, which include fatigue, decreased appetite, disturbed sleep, changes in body composition, difficulty thinking, pain, and depressed mood. These symptoms, hereafter referred to as cancer treatment related symptoms (CTRS), occur independently of chemotherapy drug class and have a profound effect on physical functioning and quality of life (QOL) , making their prevention and/or treatment essential components of cancer care. We propose that in order to develop successful strategies to prevent or treat CTRS, we need to understand the etiological mechanisms of CTRS at molecular and cellular levels. We hypothesize that mechanistically distinct cytotoxic chemotherapeutic agents trigger CTRS because they share a common ability to increase the production of the pro-inflammatory cytokine IL-1b. There are several lines of evidence that support our hypothesis. First, CTRS are remarkably similar to the symptoms associated with sickness behavior, the expected physiological response to infection or tissue damage caused by systemic increases in IL-1b. Second, in a mouse model of CTRS we have shown that peak CTRS are associated with systemic increases in IL-1. Third, using murine macrophages as a model system, we have shown that mechanistically distinct cytotoxic chemotherapeutic agents can stimulate IL-1 production and secretion in a 3-step process. The first signal, delivered to macrophages by the cytotoxic effects of the chemotherapeutic agent, primes these cells to express pro-IL-1b directly and through release of endogenous activators of Toll-like receptors (TLRs). The second signal results from the activation of ZAK, a MAP3K activated by the chemotherapeutic agent, that prolongs and intensifies the activation of JNK and p38 MAPK and synergizes with NF-kB to amplify the expression of pro-IL-1b. The third signal delivered by chemotherapeutic agent converts pro-IL-1b to its biologically active form IL-1b by inducing the formation of the NLRP3 inflammasome complex. Importantly, secretion of IL-1 in response to the chemotherapeutic agent depends critically on the NLRP3 inflammasome components ASC, CASP1, and NLRP3. The purpose of this 4-year study is to determine whether mechanistically distinct cytotoxic chemotherapeutic agents trigger CTRS because they share a common ability to increase the production of IL-1b. If proven, the various steps of the IL-1b signaling cascade may provide important targets for intervention to prevent or treat CTRS. To test our hypothesis we propose the following aims: 1) Determine the molecular mechanisms underlying the induction of inflammatory cytokines by mechanistically distinct cytotoxic chemotherapeutic agents 2) Determine whether blocking ZAK Signaling reduces CTRS. 3) Determine whether disruption of the NLRP3 inflammasome reduces CTRS. PUBLIC HEALTH RELEVANCE: Patients undergoing chemotherapy experience treatment-related symptoms, such as fatigue, malaise, decreased appetite, sleep disturbance, difficulty thinking, anemia, pain, depressed mood, and changes in body composition. The goals of this proposal are to elucidate the molecular and cellular basis of these symptoms and to test novel strategies for prevention and treatment of chemotherapy-related symptoms.